Ablating Adult Neural Stem Cells Improves Synaptic and Cognitive Functions in Alzheimer Models

Abstract

Summary Adult neurogenesis is impaired in the hippocampus of patients with Alzheimer disease (AD) as well as AD models. However, it is far from clear how modulating adult neurogenesis affects AD neuropathology. We confirm that adult hippocampal neurogenesis is impaired in two AD models. Surprisingly, however, cognitive functions are improved in AD models after ablating adult neural stem cells (aNSCs). Ablation of aNSCs does not affect the levels of amyloid β but restores the normal synaptic transmission in the dentate gyrus (DG) granule cells of AD models. Furthermore, calbindin depletion in the DG of AD mice is ameliorated after aNSC ablation, and knocking down calbindin abolishes the effects of aNSC ablation on synaptic and cognitive functions of AD mice. Together, our data suggest that cognitive functions of AD mice are improved after aNSC ablation, which is associated with the restoration of synaptic transmission in the DG granule cells with calbindin as an important mediator.

Response to questioning the evidence for a Janus-faced nature of adult neurogenesis in Alzheimer's disease

“…Recently, we examined the effects of inhibiting AHN on synaptic and cognitive functions in AD mice by using two AD models with two approaches to inhibit AHN. Our data suggest that inhibiting AHN improved synaptic and cognitive functions in AD mice (Zhang et al, 2021). In a previous study, Hollands et al reported that depletion of adult neurogenesis exacerbates cognitive deficits in AD by compromising hippocampal inhibition (Hollands et al, 2017).…”

“…This concern is actually another reason why we tried to evaluate the effects of inhibiting AHN on pathology and memory of AD mice in different models, and with different approaches. As shown in Figure 7I in our paper ( Zhang et al., 2021 ), deleting AHN with GFAP-TK/GCV improved memory in hAPP-J20 mice as well, and there was only a short period of time following the GCV treatment before behavioral tests. This effect was also in line with the results of MAM treatment in hAPP-J20 mice as shown in Figure 3 in our paper.…”

“…Recently, we examined the effects of inhibiting AHN on synaptic and cognitive functions in AD mice by using two AD models with two approaches to inhibit AHN. Our data suggest that inhibiting AHN improved synaptic and cognitive functions in AD mice ( Zhang et al., 2021 ). In a previous study, Hollands et al.…”

ErbB4 mediates amyloid β‐induced neurotoxicity through JNK/tau pathway activation: Implications for Alzheimer's disease

“…Brain sections were incubated with mouse anti‐parvalbumin antibody (1:2000, Swant, Marly, Switzerland) followed by incubation with the corresponding anti‐mouse antibody conjugated to FITC (1:250, Vector Laboratories). Quantifications were as described previously with modifications (Francis, 2003; Pan et al, 2016; Zhang et al, 2018; Zhang et al, 2021). PV + cells in the hippocampus and DG were counted by collecting four matched sections spanning the bregma (−1.46 and −3.16 mm) with a 40× objective lens on a fluorescent microscope (Olympus BX53).…”

Questioning the evidence for a Janus-faced nature of adult neurogenesis in Alzheimer’s disease

“…In contrast, a recent study by Zhang et al. suggests that ablating neurogenesis improves synaptic and cognitive function in FAD mice ( Zhang et al., 2021 ). Upon closer examination of the experimental approach, we raise questions concerning the study design and the authors’ interpretation of the results, and thus, reveal critical differences between this study and the existing body of literature (see for example [ Choi et al., 2018 ; Hollands et al., 2017 ]).…”